NO319823B1 - Polymorphs of telmisartan, processes for their preparation and their use for the preparation of a drug - Google Patents
Polymorphs of telmisartan, processes for their preparation and their use for the preparation of a drug Download PDFInfo
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- NO319823B1 NO319823B1 NO20013560A NO20013560A NO319823B1 NO 319823 B1 NO319823 B1 NO 319823B1 NO 20013560 A NO20013560 A NO 20013560A NO 20013560 A NO20013560 A NO 20013560A NO 319823 B1 NO319823 B1 NO 319823B1
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- telmisartan
- organic solvent
- water
- formic acid
- ethyl acetate
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- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 title claims description 93
- 239000005537 C09CA07 - Telmisartan Substances 0.000 title claims description 46
- 229960005187 telmisartan Drugs 0.000 title claims description 46
- 238000000034 method Methods 0.000 title claims description 15
- 239000003814 drug Substances 0.000 title description 3
- 229940079593 drug Drugs 0.000 title 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 21
- 235000019253 formic acid Nutrition 0.000 claims description 21
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 8
- 230000004048 modification Effects 0.000 claims description 7
- 238000012986 modification Methods 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229940126601 medicinal product Drugs 0.000 claims description 2
- 238000002076 thermal analysis method Methods 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000011031 large-scale manufacturing process Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000007786 electrostatic charging Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 206010019909 Hernia Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 229940123073 Angiotensin antagonist Drugs 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000000646 scanning calorimetry Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- ZZIZZTHXZRDOFM-XFULWGLBSA-N tamsulosin hydrochloride Chemical compound [H+].[Cl-].CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-XFULWGLBSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 208000026533 urinary bladder disease Diseases 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Engineering & Computer Science (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Ophthalmology & Optometry (AREA)
- Hospice & Palliative Care (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Vascular Medicine (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
Oppfinnelsen vedrører polymorfer av 4'-[2-n-propyl-4-metyl-6-{1-metyl-benzimidazol-2-yl)-benzimidazol-1 -ylmetyl]bifenyl-2-karboksylsyre {INN: telmisartan), spesielt den polymorfe form B, blandinger av polymorfene, fremgangsmåter for fremstilling av form B-inneholdende telmisartan, samt deres anvendelse til fremstilling av legemidler. The invention relates to polymorphs of 4'-[2-n-propyl-4-methyl-6-{1-methyl-benzimidazol-2-yl)-benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid (INN: telmisartan), in particular the polymorphic form B, mixtures of the polymorphs, methods for the production of form B-containing telmisartan, as well as their use in the production of pharmaceuticals.
Bakgrunn for oppfinnelsen Background for the invention
Forbindelsen telmisartan er kjent fra europeisk patent EP 505 314 B1 og oppviser følgende kjemiske struktur: The compound telmisartan is known from European patent EP 505 314 B1 and has the following chemical structure:
Telmisartan og dets fysiologisk akseptable salter, har verdifulle farmakologiske egenskaper. Telmisartan utgjøren angiotensin-antagonist, spesielt en angiotensin-ll-antagonist, som på grunn av sine farmakologiske egenskaper kan finne anvendelse til behandling av for eksempel hypertoni og hjertesvikt, til behandling av iskemiske perifere gjennomblødningsforstyrrelser, myokardiell iskemi (angina), til forhindring av hjertesviktprogresjon etter myokardinfarkt, til behandling av diabetisk neuropati, glaukom, gastrointestinale sykdommer, samt blæresykdommer. Andre mulige terapiområder er å finne i EP 502314 B1, som herved med hele sitt innhold inkorporeres i foreliggende beskrivelse. Telmisartan and its physiologically acceptable salts have valuable pharmacological properties. Telmisartan constitutes an angiotensin antagonist, in particular an angiotensin-II antagonist, which due to its pharmacological properties can be used for the treatment of, for example, hypertension and heart failure, for the treatment of ischemic peripheral blood flow disorders, myocardial ischemia (angina), for the prevention of heart failure progression after myocardial infarction, for the treatment of diabetic neuropathy, glaucoma, gastrointestinal diseases and bladder diseases. Other possible areas of therapy can be found in EP 502314 B1, which is hereby incorporated with its entire content into the present description.
I løpet av telmisartan-syntesen foretas forsåpning av tert-butylesteren (II) ifølge reaksjonsskjema 1 som avsluttende syntesetrinn. During the telmisartan synthesis, saponification of the tert-butyl ester (II) is carried out according to reaction scheme 1 as the final synthesis step.
Reaksjonsskjema 1: Reaction scheme 1:
Den tilsvarende eksperimentelle arbeidsforskrift som kan utføres i laboratorieskala, finnes i EP 502314 B1. Imidlertid var overgangen av de allerede kjente syntese-metoder til en storteknisk fremstillingsprosess ikke gjennomførbar uten problemer. Telmisartan syntetisert storteknisk ifølge Reaksjonsskjema 1, dannes etter opparbeidning i form av et produkt som for en avsluttende rensing, må underkastes et ytterligere krystallisasjonstrinn. Ved nevnte, ubetinget nødvendige krystallisasjonstrinn, førte morfologien av det utkrystalliserende sluttprodukt til uventede vanskeligheter. The corresponding experimental work regulations that can be carried out on a laboratory scale can be found in EP 502314 B1. However, the transition from the already known synthesis methods to a large-scale manufacturing process was not feasible without problems. Telmisartan, synthesized technically according to Reaction Scheme 1, is formed after processing in the form of a product which, for a final purification, must be subjected to a further crystallization step. In the aforementioned, absolutely necessary crystallization step, the morphology of the crystallized end product led to unexpected difficulties.
Produktet som faller ut som faststoff i form av lange nåler, lar seg bare vanskelig filtrere, vaske og isolere, utmerker seg dessuten med en lang tørketid på grunn av innsluttet løsningsmiddel, og danner store, meget hårde brokker under tørkeprosessen. En knusing av disse brokkene fører til et tørt pulver som oppviser en høy tendens til elektrostatisk oppladning og som praktisk talt ikke har risleevne. The product, which falls out as a solid in the form of long needles, can only be filtered, washed and isolated with difficulty, it also has a long drying time due to the contained solvent, and forms large, very hard hernias during the drying process. A crushing of these hernias leads to a dry powder which shows a high tendency to electrostatic charging and which has practically no trickling ability.
Ovennevnte ugunstige egenskaper ved et produkt viser seg ved den stortekniske fremstilling av en forbindelse alltid å være til stor hindring, idet den reproduserbare fremstilling i større mengder og høy renhet, bare er mulig gjennom store vanskeligheter eller ekstraordinær, sterk teknisk innsats. The above-mentioned unfavorable properties of a product always prove to be a major obstacle in the large-scale production of a compound, since the reproducible production in large quantities and high purity is only possible through great difficulties or extraordinary, strong technical effort.
Det er således foreliggende oppfinnelses oppgave å tilveiebringe telmisartan i en form som muliggjør den storteknisk gjennomførbare syntese, opparbeidning, rensing og isolering av telmisartan, hvor de ovennevnte ulemper overvinnes. It is thus the task of the present invention to provide telmisartan in a form which enables the technically feasible synthesis, processing, purification and isolation of telmisartan, where the above-mentioned disadvantages are overcome.
Detaljert beskrivelse av oppfinnelsen Detailed description of the invention
Det har nå overraskende vist seg at telmisartan som faststoff, kan foreligge i forskjellige krystallmodifikasjoner. Alt etter anvendt krystallisasjonsprosess, lar det seg overføre i to forskjellige polymorfe former A og B. It has now surprisingly been shown that telmisartan as a solid can exist in different crystal modifications. Depending on the crystallization process used, it can be transferred in two different polymorphic forms A and B.
Ved polymorf A dreier det seg om den kjente tilgjengelige form av telmisartan, som forårsaker de ovennevnte vanskeligheter ved den stortekniske fremstilling, resp. rensing, isolering og tørking av produktet. In the case of polymorph A, it concerns the known available form of telmisartan, which causes the above-mentioned difficulties in the large-scale production, resp. cleaning, isolation and drying of the product.
Den overraskende polymorfe form B av telmisartan oppviser derimot nesten ingen tilbøyelighet til elektrostatisk oppladning, lar seg lett avsuge, sentrifugere, vaske og tørke, og har risleevne også uten forminskning. The surprisingly polymorphic form B of telmisartan, on the other hand, shows almost no tendency to electrostatic charging, can be easily aspirated, centrifuged, washed and dried, and has trickling ability even without shrinkage.
For fremstilling av den polymorfe form B av telmisartan, benyttes i henhold til oppfinnelsen følgende fremgangsmåte. For the production of the polymorphic form B of telmisartan, the following method is used according to the invention.
I et passende dimensjonert røreverkapparat tas telmisartan-råprodukt (krystaliisert for eksempel fra dimetylformamid, dimetylacetamid eller lignende), eventuelt med 1 -5 vekt%, fortrinnsvis med 3 vekt%, aktivkull, opp i en egnet løsningsmiddelblanding bestående av vann, maursyre og et egnet organisk løsningsmiddel og løses deretter ved øket temperatur, fortrinnsvis en temperatur på 50-90°C, særlig foretrukket ved 60-80°C. In a suitably sized agitator, telmisartan raw product (crystallized for example from dimethylformamide, dimethylacetamide or the like), optionally with 1-5% by weight, preferably with 3% by weight, activated charcoal, is taken up in a suitable solvent mixture consisting of water, formic acid and a suitable organic solvent and is then dissolved at an increased temperature, preferably a temperature of 50-90°C, particularly preferred at 60-80°C.
Vesentlig ifølge oppfinnelsen er bruken av løsningsmiddelblandingen maursyre/vann med et organisk løsningsmiddel, som ifølge oppfinnelsen må oppfylle følgende kriterier. Det må være i stand til dannelse av en løsning med blandingen maursyre/vann. Det må i stor grad være kjemisk inert overfor blandingen maursyre/vann og det må kunne skilles fra blandingen maursyre/vann ved destillasjon. Organiske karboksylsyreestere, ketoner eller etere kan finne anvendelse. Som eksempel kan nevnes aceton, metyletylketon, metylacetat, etylacetat, etylformiat, etylenglykol-dimetyleter eller tetrahydrofuran. Foretrukket i henhold til oppfinnelsen er aceton, metyletylketon, metylacetat, etylacetat, THF, og særlig foretrukket er etylacetat. Essential according to the invention is the use of the solvent mixture formic acid/water with an organic solvent, which according to the invention must meet the following criteria. It must be capable of forming a solution with the formic acid/water mixture. It must be largely chemically inert to the formic acid/water mixture and it must be able to be separated from the formic acid/water mixture by distillation. Organic carboxylic acid esters, ketones or ethers can be used. Examples include acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, ethyl formate, ethylene glycol dimethyl ether or tetrahydrofuran. Preferred according to the invention are acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, THF, and particularly preferred is ethyl acetate.
Løsningsmiddelblandingen bør i henhold til oppfinnelsen være sammensatt av 0,3-0,7 L vann, 10-15 mol maursyre og 0,3-0,9 L av det organiske løsningsmiddel per mol telmisartan. Foretrukket er et forhold på 0,4-0,6 L vann, 11-13 mol maursyre og 0,4-0,7 L av det organiske løsningsmiddel per 1 mol telmisartan. Særlig foretrukket er et forhold på ca. 0,5 L vann, ca. 11,5-12 mol maursyre og ca. 0,5 L av det organiske løsningsmiddel per 1 mol telmisartan. According to the invention, the solvent mixture should be composed of 0.3-0.7 L of water, 10-15 mol of formic acid and 0.3-0.9 L of the organic solvent per mol of telmisartan. A ratio of 0.4-0.6 L of water, 11-13 mol of formic acid and 0.4-0.7 L of the organic solvent per 1 mol of telmisartan is preferred. Particularly preferred is a ratio of approx. 0.5 L water, approx. 11.5-12 mol formic acid and approx. 0.5 L of the organic solvent per 1 mole of telmisartan.
I henhold til oppfinnelsen blir den oppnådde løsning etter den innledningsvis nevnte oppvarming, filtrert og ettervasket med en blanding av ovennevnte organiske løsningsmiddel og maursyre. Per mol telmisartan kan vaskeløsningen inneholde 0,3-1,0 mol, fortrinnsvis 0,4-0,6 mol, særlig foretrukket ca. 0,5 mol maursyre. Mengden av vaskeløsning avgjøres naturligvis av mengden av det oppløste telmisartan. I henhold til oppfinnelsen tilsettes per mol telmisartan 0,1-0,4, fortrinnsvis 0,15-0,3, særlig foretrukket 0,2 L av det organiske løsningsmiddel. According to the invention, the solution obtained after the initially mentioned heating, is filtered and washed with a mixture of the above-mentioned organic solvent and formic acid. Per mol of telmisartan, the washing solution can contain 0.3-1.0 mol, preferably 0.4-0.6 mol, particularly preferably approx. 0.5 mol of formic acid. The amount of washing solution is naturally determined by the amount of dissolved telmisartan. According to the invention, 0.1-0.4, preferably 0.15-0.3, particularly preferably 0.2 L of the organic solvent is added per mole of telmisartan.
Etter ettervasking av filterresten med den ovenfor beskrevne vaskeløsning, avdestilleres det organiske løsningsmiddel mest mulig fullstendig under samtidig tilførsel av vann. Derved holdes temperaturen innen området 60-100°C, fortrinnsvis mellom 70-100°C. Den totalt tilførte vannmengde tilsvarer i det vesentlige total- mengden av avdestillert løsningsmiddel. En praktisk talt fullstendig avdestillering av det organiske løsningsmiddel er i henhold til oppfinnelsen ønskelig. Destillasjonen bringes derfor så langt at også vann, tildels azeotropisk, avdestilleres. Det avdestillerte organiske løsningsmiddel kan eventuelt etter fraskilling av vannfasen, benyttes igjen i påfølgende omsetninger. After washing the filter residue with the washing solution described above, the organic solvent is distilled off as completely as possible while simultaneously supplying water. The temperature is thereby kept within the range 60-100°C, preferably between 70-100°C. The total amount of water added essentially corresponds to the total amount of distilled solvent. A practically complete distillation of the organic solvent is desirable according to the invention. The distillation is therefore carried so far that water is also distilled off, partly azeotropically. The distilled organic solvent may, after separation of the water phase, be used again in subsequent reactions.
For utfelling av telmisartan-polymorf B, foretas en nedkjøling til temperatur-området 15-60°C, fortrinnsvis til 20-30°C, og utfelling med base. Mengden nødvendig base er avhengig av mengden av den anvendte maursyre. Fortrinnsvis tilsettes 0-2 mol mindre base enn den maursyre som er tilstede. Særlig foretrukket tilsettes 0,3-1,5 mol mindre base enn den maursyre som er tilstede. Høyst foretrukket tilsettes 0,5-1 mol mindre base enn den maursyre som er tilstede. Som base kommer så vel vandige løsninger av kaliumhydroksyd, natriumhydroksyd, litiumhydroksyd eller ammoniakk, i betraktning. Dessuten kan det anvendes egnede organiske baser som trietylamin, diisopropyletylamin eller også DBU (diazabicyklo-undecen). Særlig foretrukket som baser er de ovenfor nevnte vandige løsninger av kaliumhydroksyd, natriumhydroksyd, litiumhydroksyd eller ammoniakk, hvorav de vandige løsninger av ammoniakk tilkommer en særlig betydning. Det utfelte produkt avsentrifugeres, vaskes med vann og tørkes på vanlig måte i vakuum ved 120-125°C. En prøve uttatt direkte etter sentrifugeringen og tørket i tynne skikt i laboratoriet i et omlufts-tørkeskap, oppviser typisk et innhold på 95-99% av krystallmodifikasjon B. For precipitation of telmisartan polymorph B, cooling to the temperature range 15-60°C, preferably to 20-30°C, and precipitation with base is carried out. The amount of base required depends on the amount of formic acid used. Preferably, 0-2 mol less base than the formic acid present is added. Particularly preferably, 0.3-1.5 mol less base than the formic acid present is added. Most preferably, 0.5-1 mol less base than the formic acid present is added. As a base, aqueous solutions of potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia also come into consideration. In addition, suitable organic bases such as triethylamine, diisopropylethylamine or also DBU (diazabicycloundecene) can be used. Particularly preferred as bases are the above-mentioned aqueous solutions of potassium hydroxide, sodium hydroxide, lithium hydroxide or ammonia, of which the aqueous solutions of ammonia are particularly important. The precipitated product is centrifuged off, washed with water and dried in the usual way in a vacuum at 120-125°C. A sample taken directly after the centrifugation and dried in thin layers in the laboratory in a circulating air drying cabinet, typically shows a content of 95-99% of crystal modification B.
Etter sentrifugeringen begynner produktet, avhengig av temperatur, pH, oppholdstid og vanninnhold, mot slutten av tørkingen delvis å omvandles til modifikasjon A. Ved driftssatser oppnås derfor etter tørking forhold mellom form A og form B på i beste fall ca. 10:90, men også forhold på 60-40. After centrifugation, the product, depending on temperature, pH, residence time and water content, begins to partially convert to modification A towards the end of drying. At operating rates, therefore, after drying, a ratio between form A and form B of at best approx. 10:90, but also ratios of 60-40.
Likevel garanterer også et slikt lavt innhold av form B de ved den stortekniske fremstilling nødvendige positive produktegenskaper {f. eks. liten tendens til elektrostatisk oppladning, liten tendens til klumpdannelse, risleevne, etc). Hva som i henhold til oppfinnelsen er vesentlig ved ovennevnte krystallisasjonsprosess, er at det først dannes utelukkende form B med dens karakteristisk makroskopiske krystallform. Denne makroskopiske krystallform opprettholdes i stor grad under tørkebetingelsene på tross av partiell mikroskopisk omdannelse i form A. Nevertheless, such a low content of form B also guarantees the positive product properties necessary for large-scale production {e.g. e.g. little tendency to electrostatic charging, little tendency to lump formation, rippling ability, etc). According to the invention, what is essential in the above-mentioned crystallization process is that only form B with its characteristic macroscopic crystal form is first formed. This macroscopic crystal form is largely maintained under drying conditions despite partial microscopic transformation into form A.
Ytterligere meget verdifulle aspekter ved fremgangsmåten ifølge oppfinnelsen Further very valuable aspects of the method according to the invention
er de høye rom-tid-utbyttene ved foreliggende prosess, samt det høye utbytte av telmisartan-renprodukt, som kan isoleres nesten kvantitativt. are the high space-time yields of the present process, as well as the high yield of telmisartan pure product, which can be isolated almost quantitatively.
Det telmisartan av form A som oppnås etter fremgangsmåter kjent i henhold til teknikkens stand, adskiller seg fra det telmisartan som oppnås i henhold til oppfinnelsen og som kjennetegnes gjennom et innhold av polymorf form B med de innledningsvis nevnte fordelaktige produktegenskaper. Ytterligere forskjeller i kjennetegn beskrives i det følgende. The telmisartan of form A which is obtained according to methods known according to the state of the art, differs from the telmisartan which is obtained according to the invention and which is characterized by a content of polymorphic form B with the initially mentioned advantageous product properties. Further differences in characteristics are described below.
Telmisartan av form A krystalliserer i lange, fine, resp. tynne, nåler, som Telmisartan of form A crystallizes in long, fine, resp. thin, needles, like
kleber filtaktig til hverandre. Krystallmodifikasjonen av telmisartan av form B danner meget kompakte, terning-til-kuleformede krystaller som oppviser sand- eller kiselgel-aktige risleforhold. stick to each other like felt. The crystalline modification of form B telmisartan forms very compact, cube-to-spherical crystals that exhibit sand or silica gel-like trickle conditions.
De to polymorfe formene A og B av telmisartan adskiller seg sterkt i deres smeltepunkt. Fonn B smelter ved 183+/-2°C (bestemt ved DSC), The two polymorphic forms A and B of telmisartan differ greatly in their melting point. Fonn B melts at 183+/-2°C (determined by DSC),
form A ved 269+/- 2°C (bestemt ved DSC). Etter smeltingen krystalliserer den lavere smeltende form B av telmisartan ut igjen som form A. Dette kommer til uttrykk ved at det endoterme maksimum ved 183+/ 2°C, bestemt ved DSC, etterfølges av et karakteristisk eksotermt maksimum som gjenspeiler seg i krystallisasjon av smeiten av form B i den høytsmeltende form A. De DSC-diagrammer (DSC=Differeiitial Scanning Calorimetry) som er oppnådd med et Mettler DSC-20, TA8000 system, er form A at 269+/- 2°C (determined by DSC). After melting, the lower-melting form B of telmisartan crystallizes out again as form A. This is expressed by the fact that the endothermic maximum at 183+/ 2°C, determined by DSC, is followed by a characteristic exothermic maximum which is reflected in crystallization of the melt of form B in the high-melting form A. The DSC diagrams (DSC=Differeiitial Scanning Calorimetry) obtained with a Mettler DSC-20, TA8000 system are
vist i Figur 1. shown in Figure 1.
Polymorfene A og B adskiller seg likeledes i deres IR-spektrum. På grunn av denne forskjell kan IR-spektroskopi eventuelt benyttes til kvantitativ bestemmelse av forholdet mellom de to krystallmodifikasjonene i sluttproduktet etter tørking. IIR-spekteret oppviser ren polymorf A et karakteristisk bånd ved 815 cm'<1>. Ved polymorf B er denne svingning forskjøvet til 830 cm'<1>. Da disse to karakteristiske bånd for polymorf A og B er tilstrekkelig separert fra hverandre, er de særlig egnet til den nevnte kvantitative bestemmelse av forholdet mellom de to krystallmodifikasjonene. Polymorphs A and B also differ in their IR spectrum. Because of this difference, IR spectroscopy can possibly be used for quantitative determination of the ratio between the two crystal modifications in the final product after drying. The IIR spectrum of pure polymorph A shows a characteristic band at 815 cm'<1>. In the case of polymorph B, this oscillation is shifted to 830 cm'<1>. As these two characteristic bands for polymorphs A and B are sufficiently separated from each other, they are particularly suitable for the aforementioned quantitative determination of the ratio between the two crystal modifications.
Den IR-spektroskopiske karakterisering av de to polymorfe formene A og B, The IR spectroscopic characterization of the two polymorphic forms A and B,
ble foretatt med Nicolet FTIR Spectrometer Magna - IR 550 i KBr (2,5 umol per 300 mg KBr; Nicolet software package, OMNIC, versjon 1.20). was performed with Nicolet FTIR Spectrometer Magna - IR 550 in KBr (2.5 umol per 300 mg KBr; Nicolet software package, OMNIC, version 1.20).
Oe etterfølgende eksempler tjener til illustrasjon av de eksempelvis gjennom-førte rense- og krystallisasjonsmetoder for fremstilling av den polymorfe form B av telmisartan. De er kun å forstå som mulige eksempelvis angitte fremgangsmåter, uten å begrense oppfinnelsens ramme. The following examples serve to illustrate the purification and crystallization methods carried out, for example, for the production of the polymorphic form B of telmisartan. They are only to be understood as possible, for example, specified methods, without limiting the scope of the invention.
Eksempel 1 Example 1
I et 1200 L røreverksapparat ble det anbragt 205,6 kg telmisartan-omkrystallisat (omkrystallisert fra dimetylformamid eller dimetylacetamid), 6,2 kg aktivkull, 205,6 L vann, 211,6 kg maursyre (99-100%) og 205,6 L etylacetat. Det ble omrørt i 1 time ved 70-80°C, og deretter filtrert over i et annet 1200 L røreverks-apparat og ettervasket med en blanding av 82,2 L etylacetat og 9,2 kg maursyre (99-100%). Under samtidig innføring av 308 L vann, avdestilleres ved 80-100°C, ca. 205.6 kg of telmisartan recrystallized (recrystallized from dimethylformamide or dimethylacetamide), 6.2 kg of activated carbon, 205.6 L of water, 211.6 kg of formic acid (99-100%) and 205.6 L ethyl acetate. It was stirred for 1 hour at 70-80°C, and then filtered into another 1200 L stirrer apparatus and washed with a mixture of 82.2 L ethyl acetate and 9.2 kg of formic acid (99-100%). During the simultaneous introduction of 308 L of water, distilled off at 80-100°C, approx.
308 L løsningsmiddel. Deretter foretas avkjøling til 20-30°C og utfelling ved innføring av 313 kg 25% ammoniakkløsning. Det utfelte produkt frasentrifugeres, vaskes med vann og tørkes ved 120-125°C. 308 L solvent. Cooling to 20-30°C is then carried out and precipitation by introducing 313 kg of 25% ammonia solution. The precipitated product is centrifuged off, washed with water and dried at 120-125°C.
Utbytte: 200 kg telmisartan (97,3% av det teoretiske). Yield: 200 kg of telmisartan (97.3% of the theoretical).
Eksempel 2 Example 2
I et 1200 L røreverksapparat ble det anbragt 185 kg telmisartan-omkrystallisat (omkrystallisert fra dimetylformamid eller dimetylacetamid), 5,6 kg aktivkull, 185 L vann, 190,4 kg maursyre (99-100%) og 185 L tetrahydrofuran. Det ble omrørt i 1 time ved 60-70°C, og deretter filtrert over i et annet 1200 L røreverksapparat og ettervasket med en blanding av 74 L tetrahydrofuran og 8,3 kg maursyre (99-100%). Under samtidig innføring av 278 L vann, avdestilleres ved 70-100°C, ca. 308 L løsningsmiddel. Deretter foretas avkjøling til 20-30°C og utfelling ved innføring av 281,5 kg 25% ammoniakkløsning. Det utfelte produkt frasentrifugeres, vaskes med vann og tørkes ved 120-125°C. 185 kg of telmisartan recrystallisate (recrystallized from dimethylformamide or dimethylacetamide), 5.6 kg of activated carbon, 185 L of water, 190.4 kg of formic acid (99-100%) and 185 L of tetrahydrofuran were placed in a 1200 L mixer apparatus. It was stirred for 1 hour at 60-70°C, and then filtered into another 1200 L mixer apparatus and washed with a mixture of 74 L of tetrahydrofuran and 8.3 kg of formic acid (99-100%). During the simultaneous introduction of 278 L of water, distilled off at 70-100°C, approx. 308 L solvent. Cooling to 20-30°C is then carried out and precipitation by introducing 281.5 kg of 25% ammonia solution. The precipitated product is centrifuged off, washed with water and dried at 120-125°C.
Utbytte: 180 kg telmisartan (97,3% av det teoretiske). Yield: 180 kg of telmisartan (97.3% of the theoretical).
Eksempel 3 Example 3
I et 1200 L røreverksapparat ble det anbragt 185 kg telmisartan-omkrystallisat (omkrystallisert fra dimetylformamid eller dimetylacetamid), 5,6 kg aktivkull, 185 L vann, 190,4 kg maursyre (99-100%) og 185 L metyletylketon. Det ble omrørt i 1 time ved 60-70°C, og deretter filtrert over i et annet 1200 L røreverksapparat og ettervasket med en blanding av 74 L metyletylketon og 8,3 kg maursyre (99-100%). Under samtidig innføring av 278 L vann, avdestilleres ved 80-100°C, ca. 278 L løsningsmiddel. Deretter foretas avkjøling til 20-30°C og utfelling ved innføring av 281,5 kg 25% ammoniakkløsning. Det utfelte produkt frasentrifugeres, vaskes med vann og tørkes ved 120-125°C. 185 kg of telmisartan recrystallized (recrystallized from dimethylformamide or dimethylacetamide), 5.6 kg of activated carbon, 185 L of water, 190.4 kg of formic acid (99-100%) and 185 L of methyl ethyl ketone were placed in a 1200 L mixer apparatus. It was stirred for 1 hour at 60-70°C, and then filtered into another 1200 L mixer apparatus and washed with a mixture of 74 L of methyl ethyl ketone and 8.3 kg of formic acid (99-100%). During the simultaneous introduction of 278 L of water, distilled off at 80-100°C, approx. 278 L solvent. Cooling to 20-30°C is then carried out and precipitation by introducing 281.5 kg of 25% ammonia solution. The precipitated product is centrifuged off, washed with water and dried at 120-125°C.
Utbytte: 178 kg telmisartan (96,2% av det teoretiske). Yield: 178 kg of telmisartan (96.2% of the theoretical).
Sammenligningseksempel Comparative example
I et 1200 L røreverksapparat ble det anbragt 150 kg telmisartan (omkrystallisert fra dimetylformamid eller dimetylacetamid), 7,5 kg aktivkull, 750 L etanol og 30 kg 25% vandig ammoniakkløsning. Det ble omrørt i ca. 1 time og deretter filtrert over i et annet 1200 L røreverksapparat og ettervasket med 150 L etanol. Det oppvarmes til 70-80°C, tilsettes 35 kg iseddik og omrøres i ytterligere 1,5-2 timer ved 75-80°C. Deretter foretas avkjøling til 0-10°C og ytterligere omrøring i 2 timer. Det utfelte produkt frasentrifugeres, vaskes med 300 L etanol og med 300 L vann og tørkes ved 70-90°C. 150 kg of telmisartan (recrystallized from dimethylformamide or dimethylacetamide), 7.5 kg of activated carbon, 750 L of ethanol and 30 kg of 25% aqueous ammonia solution were placed in a 1200 L mixer apparatus. It was stirred for approx. 1 hour and then filtered into another 1200 L mixer apparatus and washed with 150 L of ethanol. It is heated to 70-80°C, 35 kg of glacial acetic acid is added and stirred for a further 1.5-2 hours at 75-80°C. Cooling to 0-10°C is then carried out and further stirring for 2 hours. The precipitated product is centrifuged off, washed with 300 L of ethanol and with 300 L of water and dried at 70-90°C.
Utbytte: 135 kg telmisartan (90% av det teoretiske) ren form A. Yield: 135 kg of telmisartan (90% of the theoretical) pure form A.
På grunn av den delvise omdannelse av den polymorfe form B til den polymorfe form A i løpet av tørkeprosessen, dannes telmisartan i henhold til fremstillingsprosessen ifølge oppfinnelsen, som rensubstans i en blanding av to polymorfe former. Dette har imidlertid ingen innvirkning på legemidlets egenskaper, idet blandingen av de polymorfe formene A og B ved fremstilling av telmisartan-tabletter, løses i 0,1 N NaOH og ved forstøvningstørking, overføres i et homogent og fullstendig amorft granulat som deretter bringes frem til de videre tablett-fremstillingstrinn. For mer fullstendige, detaljerte, opplysninger med hensyn til anvendelsen av produktet ifølge oppfinnelsen til fremstilling av et legemiddel, vises til EP 502314 B1, som herved med hele sitt innhold inkorporeres i foreliggende beskrivelse. Due to the partial conversion of the polymorphic form B to the polymorphic form A during the drying process, telmisartan is formed according to the manufacturing process according to the invention, as a pure substance in a mixture of two polymorphic forms. However, this has no effect on the properties of the medicine, as the mixture of the polymorphic forms A and B in the production of telmisartan tablets is dissolved in 0.1 N NaOH and by spray drying, transferred into a homogeneous and completely amorphous granule which is then brought to the further tablet manufacturing step. For more complete, detailed information with regard to the use of the product according to the invention for the manufacture of a medicinal product, reference is made to EP 502314 B1, which is hereby incorporated in its entirety into the present description.
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DE10153737A1 (en) * | 2001-10-31 | 2003-05-28 | Boehringer Ingelheim Pharma | Crystalline sodium salt of telmisartan, process for its preparation and its use for the manufacture of a medicament |
US6737432B2 (en) | 2001-10-31 | 2004-05-18 | Boehringer Ingelheim Pharma Kg | Crystalline form of telmisartan sodium |
PT2260833E (en) * | 2002-01-16 | 2012-12-26 | Boehringer Ingelheim Pharma | Bilayer pharmaceutical tablet comprising telmisartan and a diuretic |
DE10314702A1 (en) | 2003-03-31 | 2004-10-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for the preparation of telmisartan |
GB2414019A (en) * | 2004-05-11 | 2005-11-16 | Cipla Ltd | One-step preparation of telmisartan by condensation and hydrolysis |
KR20070061583A (en) | 2004-10-15 | 2007-06-13 | 테바 파마슈티컬 인더스트리즈 리미티드 | Process for preparing telmisartan |
US7943781B2 (en) | 2004-10-18 | 2011-05-17 | Dr. Reddy's Laboratories Limited | Process for preparing telmisartan |
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US5139114A (en) * | 1991-03-18 | 1992-08-18 | Abex Corporation | Visible brake block wear indicator |
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